PROJECT SUMMARY Candidate: Dr. Lee is an Assistant Professor of Surgery on the tenure track at The Ohio State University, with a joint appointment in the Department of Biomedical Engineering. He is surgeon scientist and holds MD, PhD, MS, and MPH degrees, and has residency training in general and cardiothoracic surgery. He has extensive experience in the development and use of tissue-engineered skeletal muscle constructs and has recently been awarded grants from NASA and the American College of Surgeons as a Principal Investigator. His long-term goal is to become an independent investigator with a focus on translational research emphasizing the clinical applications of tissue-engineered skeletal and cardiac muscle constructs. Environment: The Ohio State University Wexner Medical Center is a top ranked academic institution with a strong commitment to research and training. The Department of Surgery is ranked #14 in the country in NIH funding with over $6 million in funding annually. The department is committed to supporting the growth of promising surgeon scientists such as Dr. Lee and has provided him with the necessary support to succeed, including a separate research laboratory and office space. He will be provided 75% protected research time as part of this K08 award. He is also surrounded by three senior and successful mentors, each of whom have a long track record of continuous NIH funding and history of successfully training young scientists to become independent investigators. Dr. Lee will have a full complement of resources available to him to ensure his success. Research: This innovative proposal seeks to combine 1) Dr. Lee's expertise in the novel use of tissue-engineered skeletal muscle BioArtifical Muscles (BAMs) as an in vitro muscle model and an in vivo platform for therapeutic protein delivery and replacement graft tissue, with 2) the use of a known effective tissue repair protein, to 3) treat volumetric muscle loss (VML), a significant surgical problem with limited therapeutic options. MG53 as a tissue repair protein serves essential roles in cell membrane repair. Genetic ablation of MG53 results in defective sarcolemma repair and muscle regeneration. When administered systemically, the recombinant human MG53 (rhMG53) protein protected traumatic muscle injury and also ameliorated the pathology associated with muscular dystrophy. The scientific goal of this project is centered on testing the hypothesis that ?implantable BAMs can be engineered to secrete MG53 and enhance the tissue injury-repair and regeneration capacity associated with volumetric muscle loss?. In aim 1, he proposes to use BAMs as a model to elucidate the mechanism for MG53 secretion in response to tissue injury, and establish BAMs as a delivery vehicle for tailored secretion of MG53 to treat VML. In aim 2, he will establish the physiologic role of MG53 in muscle regeneration associated with VML and conduct proof- of-concept studies with BAM/MG53 combination to treat VML. Overall, he envisions that exploring the synergy between BAMs and MG53 will have substantial translational implications for developing a new therapeutic strategy for VML.